Project Summary Normal auditory cortex (ACX) function is crucial for the perception of speech and language. Abnormal brain wiring is thought to underlie many disorders that involve ACX such as Central Auditory Processing Disorders (CAPD), cerebral palsy, Autism Spectrum Disorder (ASD), and tinnitus. The young brain can rewire, especially during early ?critical periods? and thus is susceptible to disruptions, which can lead to permanent miswiring. Such disruptions include altered acoustic experience, early trauma, etc. These factors might interact, e.g. early insults might alter the processing of early sensory inputs, resulting in permanent wiring deficits. Thus, the onset and effect of such early influences are key to understanding normal development and a variety of disorders. Sensory experience, especially during early ?critical periods? can sculpt the connectivity of the young brain. The ?classic? ACX critical period begins with thalamic innervation of layer 4 (L4) and abnormal experience during the subsequent period e.g. through deafness, noisy environments can alter ACX circuits and function. Manipulation or replacement of sensory experience after the critical period does not lead to successful functional recovery. We recently discovered that sensory driven experience exists in ACX at much younger ages than previously thought, raising the possibility that disruption of experience during this ?pre- critical period?, which in humans occurs in utero, might fundamentally shape ACX organization, sound processing, as well as influence mechanisms during the later ?classic critical period? within L4. The early sound responsive neurons are located in the subplate, a largely transient cortical layer. Subplate neurons (SPNs) are largely absent in adults highlighting their specialized developmental role. SPNs are essential to development and plasticity in primary sensory cortices. SPNs are embedded in thalamo-cortical, intracortical, and cortico-thalamic circuits. SPN circuits are disrupted in neurodevelopmental disorders consistent with the development of sensory impairment in these disorders. As a step towards enabling functional recovery from early disruptions, we investigate the circuits of the very young ACX that allow establishment and experience dependent plasticity of connectivity and the role of SPNs to control cortical activity patterns. Based on the current wiring diagram of SPNs, we hypothesize that SPNs provide both a substrate to establish a template of intra-cortical organization and an instructive teacher-circuit to promote functional development and plasticity. We propose 3 aims: 1) Investigate how are subplate circuits modulated by early deafness and spontaneous activity. 2) How subplate circuits are modulated by sensory experience. 3) Investigate the functional consequences of early experience for hearing and ACX function. The expected insights generated from these studies will illuminate novel processes underlying auditory cortical development and contribute to the understanding of the pathophysiology of many disorders such as deafness, schizophrenia, ASD, CAPD, and language impairments. 1